Thursday, January 2, 2014

Are the hormonal side effects of dairy and its cancerous consequences even worse than they're painted by the steadily growing anti-dairy lobby?

I have to admit that I expanded Artur Vladimirovich's original question, whether I would believe that the results of a 2010 study by Maruyama K, Oshima T, Ohyama K. were a reason for concern to make it relevant for all of us - including the female SuppVersity readers. It goes without saying that we will thus have to go beyond the results of the said paper that was published in the February issue of Pediatrics international, the official journal of the Japan Pediatric Society (Maruyama. 2010) to be able to answer whether the statement "Dairy Is a Serious Threat to His Fertility and a Promoter of Her Cancer Risk!" from the headline is true, false or neither one or the other.

"[E]strogens in milk were absorbed, and gonadotropin secretion was suppressed, followed by a decrease in testosterone secretion" (Maryama. 2010) - Don't worry it looks worse than it is.

The above was the non-literal "bone of contention" Artur stumbled across on Pubmed. It's a literal quote from the conclusion of the previously mentioned Maryama paper in Pedriatrics Internatial and it is, as Artur rightly points out "a little concerting".
I have to admit. At first sight the data in Figure 1 does look disconcerting, but if you knew something about the postprandial changes in testosterone concentration you wouldn't conduct a stupid study like this, where you measure the testosterone levels fasted, 1h before the ingestion of the meal and four times every hour after the intake. And if you did that, you would realize that you've just confirmed previous research, when you realize that, both, ...

What about the kids: Maruyama et al. analyzed only the urinary hormone levels of the kids. This is at best evidence that some of the hormones are absorbed..., and excreted, again and thus not really relevant.

the gradual decrease in serum LH and FSH concentration in six out of seven men that reached a nadir 60–120 min after the milk meal, as well as

the decrease in serum testosterone concentrations which reached their minimal values ~ 120 min after the consumption of the milk in all subjects.

... are pretty much identical to what other scientists have observed before. Jeff Volek et al. (2001), vor example recorded a highly significant ~25% drop of testosterone in response to the ingestion of an allegedly significantly larger milk-free meal (1,300 kcal) that contained 11% carbohydrate, 3% protein, 86% fat and was thus considerably "fattier" than whole milk with a carbohydrate / protein / fat ratio of 33% / 19% / 49% (calculated on a per-total-energy basis).

If you take a look at the data in Figure 2 you will see that the results of the Maruyama study are not really extraordinary if you compare them to the findings Volek (2001) and Habito (2001) present in their papers. If you also take into consideration that

And what about the women: I have to apologize, but the researchers didn't find any abnormalities in the female study participants that would be of serious concern. I will still discuss the issue of possible increases in breast cancer risk due to a high dairy intake later in this article - promise!

... the diarunal rhythm, i.e. the natural ups and downs in the course of the day allow for deviations of up to 38% (in some cases more; cf. Leymarie. 1974) in serum testosterone levels over a 24h period, and

... we usually don't drink milk that comes exclusively from pregnant cows, because the commercially available milk is a mix of milk from 100s if not 1000s of cows, so that the actual hormone levels in the raw milk mix are not going to be 10x higher than in pasture-fed cows who are milked only through the first three months of a new
pregnancy (Shaw. 2007)

and compare the theories researchers like Ganmaa Davaasambuu base on the assumption that the modern milking / impregnation practice would have us consume 115-1,000pg/mL of estrone sulfate from the milk of pregnant cows instead of the regular is about 30 pg/mL that are present in the whey fraction of milk from non-pregnant cows (Ganmaa. 2001) is not supported by empirical evidence. According to Farlow, Xu & Venstra, the amount of estrone in commercially available milk:

As you can see in figure 3, the actual values are somewhere between what Ganmaa et al. tell us would be the minimal amount of estrone (E1) you'll find in whey of non-pregnant cows and the low end of the estimates Gabnmaa and her colleagues take as a basis of their theories about milk and male reproductive disorders (Ganmaa. 2011), milk and prostate cancer (Ganmaa. 2002), or milk and breast cancer (Ganmaa. 2005).

Let's put these numbers into perspective: "The level in a liter of skim milk, for example, is approximately 667 times lower than the conjugated equine estrogens in low-dose Premarin (300 g) and 1389 times lower than standard dose Premarin (625 g), which is associated with breast cancer incidence in post-menopausal women after long-term exposure." (Farlow. 2009)

It goes without saying that this discrepancy between the assumed and the real amount of estrone in milk does not exactly increase the plausibility of the assumption that the epidemiological "evidence", i.e. cherry picked associations between nationwide dairy intakes, infertility and cancer rates Ganmaa et al. cite in the respective papers, warrants the conclusion that there was a causative link between the amount of milk and milk products you consume and your likelihood of developing reproductive disorders, prostate or breast cancer.

Let's cherry pick some counter-evidence to the cherry-picked evidence!

If we simply assume that Ganmaa et al. and other researchers who subscribe to the "dairy is the devil" theory don't cite the existing counter-evidence. It should be easy to do some epidemiological cherry picking, ourselves, to support the safety of dairy, right? Right! And in the case of breast cancer, this is actually not really difficult:

-10% benign breast disease in young women with high milk intake at age 14 (Berkey. 2013)

Aside from a large body of evidence for beneficial effects, you will also find paper with results similar to those of a recent investigation into the relation of dairy consumption and breast cancer risk
in the Black Women’s Health Study by Jeanine M. Genkinger, Kepher H. Makambi, Julie R. Palmer, Lynn Rosenberg, and Lucile L. Adams-Campbell, who report that ...

If you look at the p-values (remember: p > 0.05 ➲ not significant) in Table 1 it becomes even more obvious that we are dealing with a classic null-result here. If anything you could argue that there is a minimal protective effect with a high(er) intake of skim milk.

So dairy doesn't cause breast cancer... does it make men infertile, then?

For the male fertility issue it's not exactly as easy to find our exonerating studies. In fact a relatively recent study by Afeiche et al. (2013) appears to confirm that there is a direct link between full-fat dairy consumption and compromised sperm quality in men.

These detrimental effects are yet by no means dairy exclusive (actually it should read "full-fat dairy exclusive", because most studies could not find negative effects for low fat dairy foods).

Mendiola et al. (2009), for example, observed a similar decline in sperm quality in men with a high processed meat intake and Eslamian et al. (2012) report that both, the total meat (+103%, p = 0.039) and sweets intake (+105%, p = 0.046), but not the amount of dairy the 72 asthenozoospermic men and 169 normo-zoospermic in Eslamian et al.'s case-control study consumed on a daily base were associated with a significantly higher risk of idiopathic asthenozoospermia (see Figure 4).

Saturated fat as common denominator? I know it's not popular, but processed meat and high fat dairy have a significant amount of saturated fat, which has been implicated as another correlate of reductions in sperm quality in a whole host of studies. Most recently Jensen et al. observed 38% (95% CI: 0.1%, 61%) lower sperm concentration and a 41% (95% CI: 4%, 64%) lower total sperm count in 701 young Danish men with high vs. low saturated fat intake (Jensen. 2013). In view of the less significant, but more pronounced associaton of asthenozoospermia with high sweet intakes, Eslamian et al. report in their 2012 paper, I would yet suspect that overeating and not fats or carbs are the real problem, here.

If finding evidence that the dairy ↔ infertility issue isn't an issue at all was hard, doing the same for epidemiologically established link between high(er) dairy intakes and prostate cancer is ... not virtually impossible, but significantly harder.

Last but not least, the prostate cancer issue

There is in fact a whole host of studies a litigator could chose from, if he decided to sue the dairy industry and I have to admit that I wouldn't want to wear the gown that indicates that it's up to me to decide whether evidence such as, the...

3.2x increase in advanced prostate cancer risk in men who consumed dairy products on a daily basis as adolescents, Torfadottir et al. observed in 8,894 men who were born between 1907 and 1935 in Iceland (Torfadottir. 2012),

2.2x increase in prostate cancer risk in US men who consumed 21 or more servings of dairy products per week vs. those who consumed only 5 servings/week (Tseng. 2005)

1.68x higher risk of prostate cancer risk researchers calculated in a meta-analysis of case-control studies published between 1984 and 2003 (Qin. 2007)

... is convincing enough to say: "Yes, you're right. Your prostate cancer was caused by products of the dairy industry." I mean, there is even a study by Tate et al. that was published in the August issue of Nutrition and Cancer in 2011 that appears to suggest that the link between dairy and prostate cancer is in fact one of the very few instances, where association signify causation.

Figure 5: Growth promoting effects of various substrates in an LNCaP prostate cancer cell experiment (Tate. 2011), left; Estrogen (E2 in pg/ml) levels before and after the consumption of milk of pregnant cows (Maruyama. 2010), right.

It's undebatable that the data in Figure 5 (left) leaves no doubt that bovine milk possesses greater stimulatory effect on the proliferation of LNCaP prostate cancer cells than IGF-1. It would also suggest that the relatively low levels of estrogen in bovine milk may still promote increases in serum estrogen levels that could be sufficient to cause the previously cited increases in prostate cancer risk in men with a particularly high dairy consumption.

Unfortunately, the data from the paper Artur sent me (see Figure 5, right) confirms what the proponents of dairy consumption have been saying all along (Parodi. 2012). The small amounts of estrogen (E2) in milk don't even make it into the blood stream - accordingly, the serum E2 concentration in the Maruyama study was "unchanged during the 2 h examination (before and peak: 31±4 pg/mL and 32±4 pg/mL, NS)" (Maruyama. 2010).

Let's not forget the changes in estrone and progesterone

We would thus be back to square one and our initial assumption that all that cannot be so bad, as it may have looked at first sight, if we it was not for two significant changes Maryama et al. observed in their experiment, we have hitherto ignored: The +26% and +14% increases in estrone (E1) and progesterone levels, respectively.

We have touched on estrone already. It is one of several natural estrogens and is abundant primarily during pregnancy (which explains why it's high in the milk of pregnant cows) and while the Wikipedia entry on estrone says that it was "known to cause anorexia, nausea, vomiting, and erectile dysfunction" the reference the author provides is an info-document from the United States Department of Labor.

And what about female libido? I did not forget you, ladies. The thing is with the high amount of estrone and progesterone you already have in your body, the minimal amount you may be getting from milk is probably not going to have any effects on your libido.

If you try to find corresponding evidence in peer reviewed magazines, on the other hand, you come up with a report by Jerzy Terter that was published in the British Medical Journal in October 1972 and says that estrone and estrone & testosterone have been used successfully to treat, not induce erectile dysfunction (Terter. 1972). Similar restorative effects have been reported for a combination of estrogen and progesterone, which was more effective in increasing coital frequency in male castrats than testosterone (Davidson. 1983)

Fine, libido / erectile performance shouldn't be an issue, but what about cancer?

Even if the small quantities of estrone and progesterone don't mess with your libido, this does not mean that they cannot (in the very long term) increase your risk of prostate or breast cancer, right? Since we've wantonly neglected the ladies in the previous paragraphs we'll start out with the breast cancer issue and the question: "Do progesterone or estrone increase your breast or endometrial cancer risk?"

Progesterone and breast, endometrial cancer & co: Despite the fact that studies from the 1980s show that progesterone deficiency increases the risk of developing breast cancer before menopause by more than 400% (Cowan. 1981) and in spite of recent evidence that progesterone enhances the anti-cancer effects of calcitriol (active vitamin D; cf. Lee. 2013), the rumor that progesterone / protestin based oral contraceptives would promote the growth of all sorts of cancer is tenacious.

Evidence from the early 1980 would in fact support the progesterone cancer association (Pike. 1982). If you know something about the hormonal content of the "early pill", it's no wonder that the observations Pike et al. made in the 1980s stand in contrast to the results of more recent studies on associations between oral contraceptives and breast or other forms of cancer. Studies like the one by Marchbanks et al., for example. In the corresponding paper, the researchers report ZERO increase in breast cancer risk for current oral contraceptive users and a 10% reduced breast cancer risk for those of the 4575 women with breast cancer and 4682 controls who had previously used them (Marchbanks. 2002).

It goes without saying that there are also more recent studies suggesting risk increases with oral contraceptive for various forms of cancer. The total amount, but also the type of progesteron (bovine vs. articial, sometimes much stronger progestins) do make it very unlikely that milk will promote breast cancer growth... incidentally, the previously discussed in vitro study by Tate et al. (2011) confirms that. In the said study milk may have promoted the growth of the prostate cancer cells, the breast cancer cells, the researchers tested as well, did yet not respond to be being bathed in a Petri dish full of bovine milk. Much contrary to soymilk, by the way, which promoted the growth of Tate et al.'s breast cancer cells magnificently.

Estrone and breast, endometrial cancer & co: In view of the fact that estrone is capable of binding to the estrogen receptor on breast cancer cells and considering the fact that Toniolo et al. observed in a 1995 prospective study of endogenous estrogens and breast cancer in postmenopausal women that women with estrone levels between 12.3pg/ml and 20.9pg/ml had a 3.7x elevated breast cancer risk compared to those with estrone levels of 8pg/ml or less (Toniolo. 1995). Similar results were reported only recently by Farhat et al. (2013) for premenopausal women whose breast cancer risk is 3x elevated with estrone levels of 50.39-151.39pg/ml vs. 9.05-27.86 (Farhat. 2013)

In view of the fact that I could not find a definitive number for the oral bioavailability of estrone, I had to use the C-max (max. concentration) values from a 1990 study by Aedo et al. to estimate whether the maximal amount of estrone you can find in cow's milk, i.e. ~100pg/ml could elevate a woman's E2 levels to an extend that would put her into a higher breast cancer risk category.

Why don't we use the values from the Maruyama study? I am pretty certain that it would be a bad idea to extrapolate estrogen / estrone related data from a study, where the corresponding levels were measured only in men to women. Moroever, even if we did that, we would still be faced with the problem that the peak values Maruyama et al. measured are probably irrelevant in terms of cancerous growth, which thrives in a milieu with constantly elevated estrone levels and is unlikely to grow in response to intermediate peaks that last for less than an hour.

In the said study the area under the estrone in response to the ingestion of 2.5mg of estrone-sulfate was 5.32 ng/ml per hour.

In simple (from a science point of view questionable) analogy, one liter of bovine milk from a pregnant cow in the third trimester (=highest estrone content; ca. 100pg/ml) would thus create an AUC of only 0.2pg/ml per hour. If you look at the data in Table 2 it should be obvious that this is not going to take a women from Q1 with E2 levels of 9.05–27.86pg/ml to Q3 (36.79–50.38 pg/ml) the first quartile, where the risk increase becomes statistically significant.

Honestly, I would not rely on hilariously inaccurate calculations like this, if the available epidemiological evidence I discussed before would not indicate that the consumption of bovine milk does not increase the risk of developing breast cancer, although the number of potential mechanisms, e.g. high estrogen, high estrone, high progesterone, overactivation of mTOR and IGF-1, are endless. Moreover, similar protective effects have been observed for ovarian cancer with (interestingly, they mostly ascribed to dairy calcium, though)

skim or low fat milk - 13-15% reduction, when consumed regularly

hard cheese - up to 32% reduction when consumed 2-7 days per week

cottage and ricoatte chesse - up to 24% when consumed 2-7 days per week

in a recently published study by Merrit et al. (2013). The researchers from the Harvard School of Public Health did yet also observe risk increases with high fat dairy products like cream cheese (+42%) or whole milk (+38%), which bring us back to the issue in the "saturated fat as common denominator?" box above - an issue any further analysis of which I am going to postpone to a future SuppVersity article.

If we wanted to summarize the results of our analysis, I would say that the estrogen and progesterone content in bovine milk is not much of a problem for the women. Now this begs the question, whether it is a problem for the men, whose E2 and progesterone levels were significantly, yet only shortly elevated after the consumption of the test milk in the Maruyama study.

Progesterone and prostate cancer in men: With a normal range of 0.27 – 0.9 ng/ml the progesterone levels in the Maruyama study, i.e. 0.75ng/ml are still well within the normal range, for men. This and the mere facts that

there is a host of research that confirms that the majority prostate cancer cells don't even have a progesterone receptor (Hobisch. 1997; Gregory),

render it very unlikely that the temporary progesterone peak will have any effect on prostate cancer risk - whether the potential of a belated expression of progesterone receptors, as it was observed by Bonkhoff et al. in 2001 may speed up the the proliferation of existing prostate cancer is questionable, but does not appear to be an issue with the minimal milk-induced increases in progesterone levels in the Myruyama study, anyway.

Estrone and prostate cancer risk in men: As far as the estrone levels Maruyama et al. measured in their 2010 study are concerned it is very difficult to tell, whether or not the 26% increase in E2 levels is or isn't a problem.

The estrone values in the Maruyama study are unrealistic. With a normal range of <68pg/ml the subjects in the Maruyama study would have elevated E1 levels to begin with, if the measurement was correct.

According to a study by Hsing & Comstock, prostate cancer patients have lower estrone : testosterone ratios than healthy controls (Hsing. 1993). In their 1988 paper Nomura et al. had already reported that prostate cancer patients have 26.7% lower estrone levels than healthy controls (Nomura. 1988); an observation that confirms the results of a previous analysis of estrone levels in US and Nigerian men by Ahluwalia from 1981 (Ahluwalia. 1981). In all but the Nigerians, the differences were yet not significant, which is why I would hesitate to use these observations to support the hypothesis that the changes in estrone and testosterone Maruyama et al. observed may actually protect against breast cancer.

In spite of a study by Giton et al. (2008) that implicates estrone sulfate, which happens to be elevated in the presence of high estradiol levels (probably the real culprit here) as a marker of tumor aggressiveness, it would thus appear unwarranted to worry about the estrone increase in the Maruyama study, if we focus on a 26% from a midrange estrone value (see red box above for an explanation of why I don't use the exact serum values from the study) values are even accurate.

What remains to be seen, though, is whether future epidemiological evidence will support or refute the currently heralded hypothesis that dairy consumption increases prostate cancer risk and whether we will be able to identify more feasible explanations for this relations than those that are implicated by the results Maruyama et al. present in their 2010 study.

Maybe someone finally comes up with actual evidence for the involvement of the 3ng/ml of the DHT precursor 5alpha-pregnanedione in milk (Jouan. 2006) as it was probosed by William Danby in a 2008 paper about the link between dairy intake and (pubertal) acne.

A high dairy intake...

lowers testosterone

✘

impairs libido

✘

impairs fertility

✘

disturbs regular menses

✘

promotes prostate cancer

✔

promotes breast cancer

✘

promotes any type of cancer

❓

Bottom line - What does the evidence say? This is probably the longest SuppVersity Article ever. This is why even summarizing all the points would break the mould of the short summaries of which I know that all of you love them. Therefore I decided to replace the regular text-based summary by a "graphical" one in which I list the purported pitfals of dairy consumption I discussed in the previous paragraphs and my take on the reliability of the contemporary evidence. In that, ...

✘ - indicates low-to-no evidence, while

❓ - tells you that things are not certain, yet and

✔ - marks a potential reason to stay away from dairy

If you want to learn why I chose "✘"for one and "❓"for another of the charges that are brought forward against dairy, you will yet have to read the corresponding part of this >5,000 word article - sorry ;-)

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